Acute myeloid leukemia (AML), also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. As an acute leukemia, AML progresses rapidly and is typically fatal within weeks or months if left untreated. AML is the most prevalent form of adult leukemia, particularly among the elderly and is slightly more common in men than women. There is an estimated prevalence of 30,000 cases of AML in the US and 47,000 in the EU.
The incidence of AML increases with age with a median age at diagnosis of 67 years. The global incidence CAGR for AML out to 2013 is 1.4%. An aging population, along with an increased incidence of treatment-related AML in cancer survivors, currently accounting for 10-20% of all AML cases, is expected to drive the incidence of AML. In addition, there is some geographic variation in the incidence of AML. In adults, the highest rates are seen in North America, Europe, and Oceania, while adult AML is rarer in Asia and Latin America.
AML accounts for approximately 1.2% of all cancer deaths. The 5 year survival rates for AML are low, driven by therapy failure and patients relapsing. Among patients <65 the 5 year survival rate is 34.4%, among patients >65 it is only 5%.
According to the French-American-British (FAB) classification system AML is divided into subtypes (M0 to M8), based on the type of cell from which the leukemia developed and its degree of maturity. The WHO classification incorporates of genetic abnormalities into diagnostic algorithms for the diagnosis of AML. This classification is done by examining the appearance of the malignant cells under light microscopy and by using cytogenetics and molecular genetics to characterize any underlying chromosomal abnormalities or genetic changes. The subtypes impact on prognoses, responses to therapy and treatment decisions.
The WHO subtypes are as follows:
Acute Myeloid Leukemia and Related Neoplasms
                Acute myeloid leukemia with recurrent genetic abnormalities                    AML with t(8;21)(q22;q22); RUNX1-RUNX1T1            AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11            APL with t(15;17)(q22;q12); PML-RARA            AML with t(9;11)(p22;q23); MLLT3-MLL            AML with t(6;9)(p23;q34); DEK-NUP214            AML with inv(3)(q21 q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1            AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1            Provisional entity: AML with mutated NPM1            Provisional entity: AML with mutated CEBPA                        Acute myeloid leukemia with myelodysplasia-related changes        Therapy-related myeloid neoplasms        Acute myeloid leukemia, not otherwise specified                    AML with minimal differentiation            AML without maturation            AML with maturation            Acute myelomonocytic leukemia            Acute monoblastic/monocytic leukemia            Acute erythroid leukemia                            Pure erythroid leukemia                Erythroleukemia, erythroid/myeloid                                    Acute megakaryoblastic leukemia            Acute basophilic leukemia            Acute panmyelosis with myelofibrosis                        Myeloid sarcoma        Myeloid proliferations related to Down syndrome                    Transient abnormal myelopoiesis            Myeloid leukemia associated with Down syndrome                        Blastic plasmacytoid dendritic cell neoplasm        
The efficacy of chemotherapeutic agents can be improved by improving the dosage schedule and/or using combination therapies with other compounds. Even if the concept of combining several therapeutic agents or improved dosage schedules already has been suggested, there is still a need for new and efficient therapeutic concepts for the treatment of cancer diseases, which show advantages over standard therapies.
BI 6727 is a highly potent and selective inhibitor of the serine-threonine Polo like kinase 1 (Plk1), a key regulator of cell-cycle progression. BI 6727 is a second-generation dihydropteridinone derivative with distinct pharmacokinetic (PK) properties. The problem underlying this invention was to develop improved dosage schedules for monotherapy and combinations of BI 6727 and cytarabine in AML with maximal activity and limited toxicity.
BI 6727 (I) is known as the compound N-[trans-4-[4-(cyclopropylmethyl)-1-piperazinyl]cyclohexyl]-4-[[(7R)-7-ethyl-5,6,7,8-tetrahydro-5-methyl-8-(1-methylethyl)-6-oxo-2-pteridinyl]amino]-3-methoxy-benzamide,

This compound is disclosed in WO 04/076454. Furthermore, trihydrochloride salt forms and hydrates thereof are known from WO 07/090,844. They possess properties which make those forms especially suitable for pharmaceutical use. The above mentioned patent applications further disclose the use of this compound or its monoethanesulfonate salt for the preparation of pharmaceutical compositions intended especially for the treatment of diseases characterized by excessive or abnormal cell proliferation.
Cytarabine is inter alia known by the brand names Cytosar-U, Tarabine PFS, DepoCyte and AraC. Cytarabine is mainly used in the treatment of acute myeloid leukaemia, acute lymphocytic leukaemia (ALL) and in lymphomas.